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Review
. 2008 Jan 23;2008(1):CD003122.
doi: 10.1002/14651858.CD003122.pub2.

Hormone replacement therapy for cognitive function in postmenopausal women

A Lethaby  1 , E Hogervorst, M Richards, A Yesufu, K Yaffe
Affiliations
Review

Hormone replacement therapy for cognitive function in postmenopausal women

A Lethaby et al. Cochrane Database Syst Rev. .

Abstract

Background: As estrogens have been found in animal models to be associated with the maintenance and protection of brain structures, it is biologically plausible that maintaining high levels of estrogens in postmenopausal women by medication could be protective against cognitive decline.

Objectives: To investigate the effect of ERT (estrogens only) or HRT (estrogens combined with a progestagen) in comparison with placebo in RCTs on cognitive function in postmenopausal women.

Search strategy: The CDCIG Specialized Register was searched 7 March 2006. Additional searches were made of MEDLINE (1966-2006/02); EMBASE (1985-2006/02); PsycINFO (1967-2006/02) and CINAHL (1982-2006/01).

Selection criteria: All double-blind RCTs trials of the effect of ERT or HRT on cognitive function over a treatment period of at least two weeks in postmenopausal women.

Data collection and analysis: Selection of studies, assessment of quality and extraction of data were undertaken independently by three reviewers with disagreements resolved by discussion.

Main results: In total, 24 trials were included, but only 16 (10,114 women) had analysable data. Meta-analyses showed no effects of either ERT or HRT on prevention of cognitive impairment after five and four years of treatment, respectively (odds ratio 1.34, 95% CI 0.95 to 1.9; odds ratio 1.05, 95% CI 0.72 to 1.54 respectively) (trend favouring control in both instances). Analyses assessing the effects of treatment over time found that both ERT and HRT did not maintain or improve cognitive function and may even adversely affect this outcome (WMD = -0.45, 95% CI -0.99 to 0.09; WMD = -0.16, 95% CI -0.58 to 0.26, respectively at maximum follow up). Negative effects were found for ERT after one year and HRT after three and four years of therapy. Results from smaller trials assessing effects on individual cognitive domains mostly reported no evidence of benefit.

Authors' conclusions: There is good evidence that both ERT and HRT do not prevent cognitive decline in older postmenopausal women when given as short term or longer term (up to five years) therapy. It is not known whether either specific types of ERT or HRT have specific effects in subgroups of women, although there was evidence that combined hormone therapy in similarly aged women was associated with a decrement in a number of verbal memory tests and a small improvement in a test of figural memory. There is insufficient evidence to determine whether subgroups of women using specific types of hormone therapy could benefit from treatment. It remains to be determined whether factors such as younger age (< 60 years of age), type of menopause (surgical or natural) and type of treatment (type of estrogen with or without a progestagen), mode of delivery (transdermal, oral or intramuscular) and dosage have positive effects at a clinically relevant level. In addition, whether the absence or presence of menopausal symptoms can modify treatment effects should be investigated in more detail. Large RCTs currently underway in the USA may be able to provide answers to these uncertainties by the year 2010. In the meantime, based on the available evidence, ERT or HRT cannot be recommended for overall cognitive improvement or maintenance in older postmenopausal women without cognitive impairment.

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Conflict of interest statement

None known.

Figures

1.1
1.1. Analysis
Comparison 1 The effect of ERT/HRT versus placebo on global cognition scores, Outcome 1 CAMCOG after 20 weeks of E2 versus placebo.
1.2
1.2. Analysis
Comparison 1 The effect of ERT/HRT versus placebo on global cognition scores, Outcome 2 3MSE score after CEE + MPA (variable follow up).
1.3
1.3. Analysis
Comparison 1 The effect of ERT/HRT versus placebo on global cognition scores, Outcome 3 3MSE score after CEE alone (variable follow up).
1.4
1.4. Analysis
Comparison 1 The effect of ERT/HRT versus placebo on global cognition scores, Outcome 4 Folstein Mini‐Mental State Examination with CEE alone or CEE + MPA after 3 years.
2.1
2.1. Analysis
Comparison 2 The effect of ERT/HRT versus placebo on prevention of mild cognitive impairment, Outcome 1 Mild cognitive impairment (based on WHIMS protocol).
3.1
3.1. Analysis
Comparison 3 The effect of ERT/HRT versus placebo on verbal memory and language tests, Outcome 1 Paired Associates (intermediate recall) after HRT or placebo.
3.2
3.2. Analysis
Comparison 3 The effect of ERT/HRT versus placebo on verbal memory and language tests, Outcome 2 Paired associate learning (different scoring methods immediate recall).
3.3
3.3. Analysis
Comparison 3 The effect of ERT/HRT versus placebo on verbal memory and language tests, Outcome 3 Paired Associate (delayed recall) after HRT or placebo.
3.4
3.4. Analysis
Comparison 3 The effect of ERT/HRT versus placebo on verbal memory and language tests, Outcome 4 Other Paired Associate tests.
3.5
3.5. Analysis
Comparison 3 The effect of ERT/HRT versus placebo on verbal memory and language tests, Outcome 5 Paragraph recall (immediate) after 2 to 3 months of E2 i.m. or placebo.
3.6
3.6. Analysis
Comparison 3 The effect of ERT/HRT versus placebo on verbal memory and language tests, Outcome 6 Paragraph recall (delayed) after 2 months with E2 i.m. or placebo.
3.7
3.7. Analysis
Comparison 3 The effect of ERT/HRT versus placebo on verbal memory and language tests, Outcome 7 Verbal Fluency (semantic memory).
3.8
3.8. Analysis
Comparison 3 The effect of ERT/HRT versus placebo on verbal memory and language tests, Outcome 8 Word list recall tests.
3.9
3.9. Analysis
Comparison 3 The effect of ERT/HRT versus placebo on verbal memory and language tests, Outcome 9 Wechsler Memory Scale ‐ Revised (logical memory ‐ immediate recall).
3.10
3.10. Analysis
Comparison 3 The effect of ERT/HRT versus placebo on verbal memory and language tests, Outcome 10 Wechsler Memory Scale ‐ Revised (logical memory ‐ delayed recall).
3.11
3.11. Analysis
Comparison 3 The effect of ERT/HRT versus placebo on verbal memory and language tests, Outcome 11 Wechsler Memory Scale ‐ Revised (logical memory ‐ % retained) after 10 weeks E2 transdermal or placebo.
3.12
3.12. Analysis
Comparison 3 The effect of ERT/HRT versus placebo on verbal memory and language tests, Outcome 12 Boston Naming Test after low E transdermal versus placebo.
3.13
3.13. Analysis
Comparison 3 The effect of ERT/HRT versus placebo on verbal memory and language tests, Outcome 13 PMA Vocabulary after 1+ years of HRT versus placebo.
3.14
3.14. Analysis
Comparison 3 The effect of ERT/HRT versus placebo on verbal memory and language tests, Outcome 14 Verbal Fluency ‐ letter after 1+ years of HRT versus placebo.
3.15
3.15. Analysis
Comparison 3 The effect of ERT/HRT versus placebo on verbal memory and language tests, Outcome 15 Verbal Fluency ‐ categories after 1+ years of HRT versus placebo.
3.16
3.16. Analysis
Comparison 3 The effect of ERT/HRT versus placebo on verbal memory and language tests, Outcome 16 Word list recall tests after 1+ years of HRT versus placebo (inverse variance).
4.1
4.1. Analysis
Comparison 4 The effect of ERT/HRT versus placebo on visual memory, Outcome 1 Visuo(spatial) memory tests.
4.2
4.2. Analysis
Comparison 4 The effect of ERT/HRT versus placebo on visual memory, Outcome 2 Visuospatial memory tests (inverse variance).
5.1
5.1. Analysis
Comparison 5 The effect of ERT/HRT versus placebo on speed tests, attention and manual dexterity, Outcome 1 Test of simple speed of information processing.
5.2
5.2. Analysis
Comparison 5 The effect of ERT/HRT versus placebo on speed tests, attention and manual dexterity, Outcome 2 Tests of other information processing.
5.3
5.3. Analysis
Comparison 5 The effect of ERT/HRT versus placebo on speed tests, attention and manual dexterity, Outcome 3 Attention and working memory tests after 1+ year HRT versus placebo (inverse variance).
5.4
5.4. Analysis
Comparison 5 The effect of ERT/HRT versus placebo on speed tests, attention and manual dexterity, Outcome 4 Fine Motor Speed after 1+ yrs of HRT versus placebo (inverse variance).
5.5
5.5. Analysis
Comparison 5 The effect of ERT/HRT versus placebo on speed tests, attention and manual dexterity, Outcome 5 Tests of general information processing speed and recognition.
7.1
7.1. Analysis
Comparison 7 The effect of ERT/HRT versus placebo on tests of mental rotations, Outcome 1 Mental Rotations time (120 degrees only) after 3 weeks of E2 transdermal or placebo.
7.2
7.2. Analysis
Comparison 7 The effect of ERT/HRT versus placebo on tests of mental rotations, Outcome 2 Mental Rotations number after 2 weeks of E2 transdermal or placebo.
7.3
7.3. Analysis
Comparison 7 The effect of ERT/HRT versus placebo on tests of mental rotations, Outcome 3 Card rotations after 1+ year of HRT versus placebo (inverse variance).
8.1
8.1. Analysis
Comparison 8 The effect of ERT/HRT versus placebo on accuracy, Outcome 1 Clerical speed and accuracy (# correct) after 3 months of E2 i.m. or placebo.
8.2
8.2. Analysis
Comparison 8 The effect of ERT/HRT versus placebo on accuracy, Outcome 2 Letter Cancellation (# correct) after 9 months of CEE or placebo.
8.3
8.3. Analysis
Comparison 8 The effect of ERT/HRT versus placebo on accuracy, Outcome 3 Random number generation after 3 weeks of E2 transdermal or placebo.
9.1
9.1. Analysis
Comparison 9 The effect of ERT/HRT versus placebo on executive function, Outcome 1 Wisconsin Card Sorting Test (categories) after 10 weeks E2 transdermal or placebo.
9.2
9.2. Analysis
Comparison 9 The effect of ERT/HRT versus placebo on executive function, Outcome 2 Wisconsin Card Sorting Test (perseverative responses) after 10 weeks E2 transdermal or placebo.
9.3
9.3. Analysis
Comparison 9 The effect of ERT/HRT versus placebo on executive function, Outcome 3 Wisconsin Card Sorting Test (% conceptual level responses) after 10 weeks E2 transdermal or placebo.
9.4
9.4. Analysis
Comparison 9 The effect of ERT/HRT versus placebo on executive function, Outcome 4 Weschler Adult Intelligence Scale ‐ Revised (picture arrangement) after 10 weeks E2 transdermal or placebo.
9.5
9.5. Analysis
Comparison 9 The effect of ERT/HRT versus placebo on executive function, Outcome 5 Tower of London after 3 weeks of E2 transdermal or placebo.
9.6
9.6. Analysis
Comparison 9 The effect of ERT/HRT versus placebo on executive function, Outcome 6 Abstract reasoning (DAT) after 3 months of IM E2 or placebo.
9.7
9.7. Analysis
Comparison 9 The effect of ERT/HRT versus placebo on executive function, Outcome 7 Controlled Word Association Test (COWAT) after 10 weeks E2 transdermal or placebo.
9.8
9.8. Analysis
Comparison 9 The effect of ERT/HRT versus placebo on executive function, Outcome 8 Stroop test (interference time) after 10 weeks of E2 transdermal or placebo.
9.9
9.9. Analysis
Comparison 9 The effect of ERT/HRT versus placebo on executive function, Outcome 9 Stroop (interference errors) after 10 weeks of E2 transdermal or placebo.
9.10
9.10. Analysis
Comparison 9 The effect of ERT/HRT versus placebo on executive function, Outcome 10 Trails B with either CEE + MPA or low E transdermal versus placebo.
9.11
9.11. Analysis
Comparison 9 The effect of ERT/HRT versus placebo on executive function, Outcome 11 Digits Backward after 1+ year HRT versus placebo.
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